OVERALL ? PROJECT SUMMARY The objective of the ENCORE (Encyclopedia of RNA Elements) Consortium is to develop a foundational, functional map of protein-RNA interactions of RNA binding proteins (RBPs) encoded in the human genome, and the RNA elements they bind to across the transcriptome. These RNA elements, when expressed, form the basis of co- and post-transcriptional regulation of human genes. Our strategy consists of developing and integrating a physical map of 300 RBPs in two different human cell lines with transcriptome-wide measurements of the effects of depleting these RBPs, their localization patterns and their binding preferences independent of co-factor associations. Over the past 4 years, our consortium (Burge, Graveley, Lecuyer and Yeo) has established highly efficient data production workflows of experimental methods (RNA bind-n-seq, RNA-seq, Localization and enhanced CLIP) that will enable us to immediately expand these datasets, which form a crucial and missing link to decipher the mechanisms of post-trancriptional regulation and how these impact genetic variation and disease etiology. When combined with the data we generated over the past four years, these efforts will culminate in a comprehensive map of the functional RNA elements recognized by essentially all RBPs expressed in two human cell lines, representing approximately half of the known complement of human RBPs. ENCORE will (1) generate and validate a physical resource of cell lines expressing epitope-tagged RBPs, (2) develop transcriptomics and imaging databases of these RBPs to provide simple interfaces for the community to mine this resource, (3) develop and distribute workflows for integrative analyses and shareable results from these workflows and (4) provide training and outreach to establish ENCORE annotations as the standard reference for co- and post-transcriptional research and clinical genomics efforts in the long-term.